Biology subjects

Denvir, J.

Publications and source records attributed to Denvir, J..

3 recordsLinked to original sources

bioRxiv2021

SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern induce lethal disease in K18-hACE2 transgenic mice despite convalescent plasma therapy

SARS-CoV-2 variants of concern (VoCs) are impacting responses to the COVID-19 pandemic. Here we present a comparison of the SARS-CoV-2 USA-WA1/2020 (WA-1) strain with B.1.1.7 and B.1.351 VoCs and identify significant differences in viral propagation in vitro and pathogenicity in vivo using K18-hACE2 transgenic mice. Passive immunization with plasma from an early pandemic SARS-CoV-2 patient resulted in significant differences in the outcome of VoC-infected mice. WA-1-infected mice were protected by plasma, B.1.1.7-infected mice were partially protected, and B.1.351-infected mice were not protected. Serological correlates of disease were different between VoC-infected mice, with B.1.351 triggering significantly altered cytokine profiles than other strains. In this study, we defined infectivity and immune responses triggered by VoCs and observed that early 2020 SARS-CoV-2 human immune plasma was insufficient to protect against challenge with B.1.1.7 and B.1.351 in the mouse model.

microbiology↗

bioRxiv2020

RNA-Seq data analysis of a rodent model of adolescent binge drinking reveals pathways and candidate genes involved in neuronal remodeling and neuroimmune activation

IntroductionBinge drinking is common among adolescents and young adults and is associated with an increased risk of developing alcohol use disorder (AUD) and long-term cognitive deficits. We analyzed RNA-seq data from male Sprague Dawley rats to identify candidate genes that may play a role in the acute and chronic changes in cognitive function during binge-like adolescent alcohol/EtOH exposure and after a period of abstinence. MethodsAt postnatal day (PND) 30, male rats received chronic intermittent EtOH across 16 days. RNA was extracted from hippocampal tissue and sequenced at two acute timepoints, PND 35 and PND 46, and after 24 days forced abstinence (PND 70). We processed RNA-seq data, compiled gene counts, and performed normalization and differential expression analysis (DESeq2). Gene set enrichment analysis was performed through the R package fgsea. Gene sets of the Molecular Signatures Database (MSigDB) collections were used to identify gene pathways that were dysregulated following EtOH exposure. We also evaluated overlapping gene pathways that were affected across all timepoints. ResultsMultiple gene pathway analyses revealed that EtOH has robust effects on neuroinflammation, cellular remodeling, sleep, and bioenergetics. Changes were heavily dependent on whether gene expression was assessed during acute EtOH exposure or after abstinence. Genes involved in sleep regulation were selectively impacted during the acute timepoints, whereas dysregulation of genes involved in bioenergetics were only impacted after abstinence. The most striking changes occurred in genes that regulate neuroinflammatory processes and cellular remodeling. ConclusionThese data reveal acute and chronic effects of EtOH on multiple gene pathways that persist across analytic approaches and identify genes that have increased sensitivity to EtOH. These findings contribute to our understanding of the temporal effects of adolescent EtOH exposure and how gene pathway dysregulation contributes to the protracted emergence of neuronal remodeling in the hippocampus during a critical period of brain maturation.

bioinformatics↗

bioRxiv2020

Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice

Recent literature implicates gut epithelia mucosa and intestinal microbiota as important players in post-stroke morbidity and mortality. As most studies have focused on the acute effects of stroke on gut dysbiosis, our study objective was to measure chronic, longitudinal changes in the gut microbiota and intestinal pathology following ischemic stroke. We hypothesized that mice with experimental ischemic stroke would exhibit chronic gut dysbiosis and intestinal pathology up to 36 days post-stroke compared to sham controls. Male C57BL/6J mice were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) or sham surgery. To determine the long-term effects of tMCAO on gut dysbiosis, fecal boli were collected pre- and post-tMCAO on days 0, 3, 14, and 28. Bioinformatics analysis demonstrate significant differences in abundance among Firmicutes and Bacteroidetes taxa at the phylum, family, and species levels in tMCAO compared to sham mice that persisted up to one month post-stroke. The most persistent changes in post-stroke microbial abundance were a decrease in bacteria family S24-7 and significant increases in Ruminococcaceae. Overall, these changes resulted in a persistently increased Firmicutes:Bacteroidetes ratio in stroke animals. Intestinal histopathology showed evidence of chronic intestinal inflammation that included marked increases in immune cell infiltration with mild-moderate epithelial hyperplasia and villous blunting. Increased astrocyte and microglial activity were also detected one-month post-stroke. These results demonstrate that acute, post-stroke disruption of the gut-brain-microbiota axis progresses to chronic gut dysbiosis, intestinal inflammation, and chronic neuroinflammation. Clinical PerspectivesO_LIThe microbiota-gut-brain axis, recently implicated in several neurological disorders, remains largely unexplored at chronic time points post-tMCAO. C_LIO_LIOur results demonstrate chronic gut dysbiosis, prolonged behavioral deficits, and persistent cerebral and intestinal inflammation post-tMCAO in male C57BL/6J mice. C_LIO_LIThese results suggest that manipulation of microbiota may help reduce poor outcomes after stroke and lead to improved post-stroke functional recovery. C_LI

neuroscience↗